A new mechanism for growth hormone receptor activation of JAK2, and implications for related cytokine receptors

Abstract

The growth hormone receptor was the first cytokine receptor to be cloned and crystallized, and provides a valuable exemplar for activation of its cognate kinase, JAK2. We review progress in understanding its activation mechanism, in particular the molecular movements made by this constitutively dimerized receptor in response to ligand binding, and how these lead to a separation of JAK-binding Box1 motifs. Such a separation leads to removal of the pseudokinase inhibitory domain from the kinase domain of a partner JAK2 bound to the receptor, and vice versa, leading to apposition of the kinase domains and transactivation. This may be a general mechanism for class I cytokine receptor action.

Keywords: Box1; FRET; conformational change; molecular dynamics; receptor dimer; transmembrane helix.

Figure 1. Receptor/JAK2 activation process. Cartoon of basal state (State 1) and of active state (State 2) with helix alignments for these states derived by modeling shown below each cartoon. In State 1 the pseudokinase domains inhibit their partner JAK2 kinase domains, while in the active state the pseudokinase domains are removed as a result of tilting of the receptor helices, bringing the kinase domains into proximity for trans-activation. Reproduced from Brooks et al. with permission.